Treatments targeting the luminal gut microbiota in patients with irritable bowel syndrome

Irritable bowel syndrome (IBS) is a common disorder of gut-brain interaction affecting 4% of the world's population. Patients with IBS experience chronic or recurrent abdominal pain in combination with altered bowel habits (diarrhea and/or constipation), and have reduced quality of life. Despite the high prevalence and substantial burden of IBS, its pathophysiology is incompletely understood and remains to be elucidated. The importance of the gut microenvironment has been highlighted in IBS, as there are signs that the gut microbiota of patients differs from healthy controls. Recent studies have aimed to alter the gut microbiota and thereby, attempted to alleviate gastrointestinal symptoms in IBS patients. We highlighted recent advances in common treatments that are targeting the luminal gut microbiota in IBS.     

Antinociceptive potency of enkephalins and enkephalinase inhibitors in the mouse model of colorectal distension—proof‐of‐concept

Irritable bowel syndrome (IBS) is a chronic disease characterized by abdominal pain and changes in bowel habits. Patients with IBS comprise a significant portion of attendants at the outpatient clinics. Targeting intestinal opioid receptors was found successful in alleviating pain and diarrhea—two major symptoms of IBS. In this study, we aimed to evaluate a novel potential pharmacological option: the use of enkephalinase inhibitors in therapy of visceral pain occurring in the course of IBS. We thus assessed the antinociceptive efficacy of enkephalins: Leu‐enkephalin and Met‐enkephalin, and enkephalinase inhibitors: opiorphin and sialorphin in the mouse model of visceral pain induced by colorectal distension. Leu‐enkephalin, Met‐enkephalin, and sialorphin, but not opiorphin, at the dose of 1 mg/kg injected subcutaneously potently decreased the visceromotor response to colon distension as compared to control. To conclude, enkephalinase inhibitors are worth being considered as potential therapeutics in patients with chronic abdominal pain and/or changed bowel habits, that is, suffering from IBS.     

Review article: the functional abdominal pain syndrome

Aliment Pharmacol Ther 2011; 33: 514–524

Summary

Background Functional abdominal pain syndrome (FAPS) is a debilitating disorder with constant or nearly constant abdominal pain, present for at least 6 months and loss of daily functioning. Aim To review the epidemiology, pathophysiology and treatment of FAPS. Methods A literature review using the keywords: functional abdominal pain, chronic abdominal pain, irritable bowel syndrome and functional gastrointestinal disorders. Results No epidemiological studies have focused specifically on FAPS. Estimates of prevalence range from 0.5% to 1.7% and tend to show a female predominance. FAPS pathophysiology appears unique in that the pain is caused primarily by amplified central perception of normal visceral input, rather than by enhanced peripheral stimulation from abdominal viscera. The diagnosis of FAPS is symptom‐based in accordance with the Rome III diagnostic criteria. These criteria are geared to identify patients with severe symptoms as they require constant or nearly constant abdominal pain with loss of daily function and are differentiated from IBS based on their non‐association with changes in bowel habit, eating or other gut‐related events. As cure is not feasible, the aims of treatment are reduced suffering and improved quality of life. Treatment is based on a biopsychosocial approach with a therapeutic patient–physician partnership at its base. Therapeutic options include central nonpharmacological and pharmacological modalities and peripheral modalities. These can be combined to produce an augmentation effect. Conclusion Although few studies have assessed functional abdominal pain syndrome or its treatment specifically, the treatment strategies outlined in this paper appear to be effective.     

Neurokinin-1-receptor antagonism decreases anxiety and emotional arousal circuit response to noxious visceral distension in women with irritable bowel syndrome: a pilot study

Background Irritable bowel syndrome is characterised by chronic abdominal pain and frequent comorbid anxiety. The substance P/neurokinin‐1 receptor system is implicated in the regulation of both pain and anxiety, suggesting a potential therapeutic target in IBS. Aim To determine whether inhibition of the neurokinin‐1 receptor (NK1R) will change pain ratings and brain responses to experimental visceral pain and anxiety symptoms in women with IBS or not. Methods Rome II positive IBS women were recruited for a double‐blind, placebo‐controlled, cross‐over study of NK1R antagonist AV608. Treatment periods were 3 weeks with a 2‐week washout period. Functional MRI during a visceral distension paradigm was performed before first treatment and after treatment blocks. SPM8 was used to compare brain activity during painful and nonpainful visceral stimuli in regions associated with emotional arousal and interoception. Negative affect, anxiety symptoms and pain ratings were assessed. Results Eleven subjects completed the study and eight subjects provided fMRI data. AV608, compared with placebo, was associated with reduced anxiety, negative affect, and pain ratings. During AV608 treatment, the amygdala, hippocampus and anterior cingulate gyrus showed decreased activity during visceral distension. AV608 was also associated with decreases in activity in brain regions associated with interoception (posterior insula, anterior mid‐cingulate gyrus). Conclusions Chronic treatment with AV608 in IBS is associated with improved mood and pain ratings and activity of emotional arousal related brain regions. This suggests that further exploration of NK1R antagonists is warranted in visceral pain disorders, particularly in patients with comorbid anxiety symptoms.     

Irritable bowel syndrome is strongly associated with generalized anxiety disorder: a community study

Background  No previous study has examined the comorbidity of Irritable Bowel Syndrome (IBS) and Generalized Anxiety Disorder (GAD) in a general population using standardized diagnostic methods.
Aim  To examine the prevalence, comorbidity and risk correlates of IBS and GAD in a general population.
Methods  A random community-based telephone survey was conducted. The questionnaire covered symptoms of IBS, GAD, core depressive symptoms, help-seeking behaviour and functional impairment on the Sheehan Disability Scale.
Results  A total of 2005 participants completed the interview. The current prevalence of IBS was 5.4% and the 12-month prevalence of GAD was 4%. GAD was five times more common among IBS respondents than non-IBS respondents (OR: 5.84, P  < 0.001), whereas IBS was 4.7 times more common among GAD respondents than among non-GAD respondents (OR: 6.32, P  < 0.001). Core depressive symptoms (OR: 6.25, P  < 0.01) and education level (OR: 5.918, P  = 0.021) were risk correlates of GAD among IBS respondents. Comorbid respondents were more impaired than respondents having either disorder alone, but were not more likely to seek professional help than IBS-only respondents.
Conclusion  Irritable Bowel Syndrome and GAD comorbidity was common and added to impairment in the community. The strong association between psychiatric morbidity and IBS observed in referral centres was not a consequence of increased help-seeking behaviour.     

Interaction between psychiatric and autoimmune disorders in coeliac disease patients in the Northeastern United States

Background  Previous studies yielded conflicting results regarding the presence of an association between coeliac disease (CD) and psychiatric disorders including depression. This association has not been studied in the United States.
Aim  To determine the prevalence of psychiatric and autoimmune disorders in patients with CD in the US compared with control groups.
Methods  In a case control study, the prevalence of psychiatric and autoimmune disorders was compared in 600 CD patients, 200 irritable bowel syndrome (IBS) patients and 200 healthy controls.
Results  The prevalence of depression in CD was 17.2% and was similar to that in IBS (18.5%, P = 0.74) and controls (16.0%, P = 0.79). Among CD patients, type I diabetes mellitus (DM) was identified as a significant risk factor for depression ( P < 0.01) with 37% of patients with both CD and type I DM having clinical depression.
Conclusion  The prevalence of depression in CD is similar to that in other chronic gastrointestinal diseases and healthy controls. However, there is a markedly elevated risk of depression in patients with both type I DM and CD. Differing rates of type 1 DM among coeliac populations may account for disparity in published rates of depression in patients with CD.     

Review article: gender-related differences in functional gastrointestinal disorders

Many functional gastrointestinal disorders and other chronic visceral pain disorders such as interstitial cystitis and chronic pelvic pain are more common in women than in men. In irritable bowel syndrome (IBS) there is a 2 : 1 female to male ratio in prevalence of symptoms in community samples. Female irritable bowel syndrome patients are more likely to be constipated, complain of abdominal distension and of certain extracolonic symptoms.
While animal studies have clearly demonstrated gender-related differences in pain perception and antinociceptive mechanisms, unequivocal evidence for gender-related differences in human pain perception or modulation has only been provided recently. Gender-related differences may be related to constant differences in the physiology of pain perception, such as structural or functional differences in the visceral afferent pathways involved in pain transmission or modulation, and/or they may be related to fluctuations in female sex hormones.
Preliminary evidence suggests that female irritable bowel syndrome patients show specific perceptual alterations in regards to rectosigmoid balloon distension and that they show differences in regional brain activation measured by positron emission tomography. This preliminary evidence suggests that gender-related differences in symptoms and in the perceptual responses to visceral stimuli exist in IBS patients and can be detected using specific stimulation paradigms and neuroimaging techniques.     

Nondigestive symptoms in non-erosive reflux disease: nature, prevalence and relation to acid reflux

Background Nondigestive symptoms are frequent in the irritable bowel syndrome (IBS). Aim To characterize nondigestive symptoms in non‐erosive gastro‐oesophageal reflux disease (NERD) patients, as features of IBS are common in patients with NERD. Methods A prospective, case–control study. NERD was defined in patients with reflux symptoms, a normal oesophageal mucosa and oesophageal pH <4 for ≥5% of the time during 24‐h pH monitoring. Nondigestive symptoms were scored on validated scales of somatic pain, urinary, sleep and neurasthenia. IBS was defined by the Rome I criteria. Results pH‐positive NERD patients (n = 326) scored significantly higher than controls (nonpatient hospital visitors; n = 174) on all scales. The scores of pain, sleep and neurasthenia were highly specific in the discrimination of NERD patients from controls. In patients, nondigestive symptoms were independently associated with age, reflux symptoms severity and IBS status, but not with oesophageal acid exposure. NERD patients who met diagnostic criteria for IBS (49%) scored significantly higher on all the nondigestive symptoms scales than those had not met [IBS(?)]. Yet, IBS(?) patients scored significantly higher than controls on all scales. Conclusions Nondigestive symptoms were highly prevalent in NERD patients and were specific in their discrimination from controls. Nondigestive symptoms correlated with reflux symptoms and were predicted by IBS status.     

肠易激综合征的主要致病因素及中医药治疗

肠易激综合征 (Irritable bowel syndrome,IBS) 是一种慢性复发性功能性胃肠道疾病。IBS 的病理生理学尚未完全了解,并且它的致病是多因素的。IBS有许多致病因素,这些因素不一定全部存在于每个患者中,但都对IBS的发病发挥着重要作用。IBS 的典型临床表现是因排便形式的改变而产生的不适或腹痛。IBS 的及时诊断很重要,因此可以引入可缓解症状（腹泻、便秘、疼痛）的治疗方法。本文整理了 IBS 在现有研究中可能致病的发病因素,为研究者在研究治疗 IBS 药物的新靶标上提供更多的思路,同时总结了 IBS 在中医诊断下的证候,对中医药治疗 IBS 进行综述。     

Randomised clinical trial: otilonium bromide improves frequency of abdominal pain, severity of distention and time to relapse in patients with irritable bowel syndrome

Aliment Pharmacol Ther 2011; 34: 432–442

Summary

Background Otilonium bromide (OB) is a spasmolytic agent that blocks L‐Type Calcium channels in human colonic smooth muscle. Aim To study the efficacy of OB in symptom control in irritable bowel syndrome (IBS). Methods A total of 356 patients (46.16 ± 19 years, 71% female) with IBS participated in a double‐blind, randomised, parallel placebo‐controlled phase IV study. OB (40 mg t.d.s.) or placebo was administered for 15 weeks, and follow‐up was extended 10 additional weeks. Results Otilonium bromide (n = 179) and placebo (n = 177) groups had comparable demographics, symptom severity and IBS subtype. Both OB and placebo reduced abdominal pain and IBS symptoms. The effect of OB was significantly greater than placebo in the reduction of weekly frequency of episodes of abdominal pain at the end of treatment period (primary endpoint, ?0.90 ± 0.88 vs. ?0.65 ± 0.91, P = 0.03), reduction of abdominal bloating (?1.2 ± 1.2 vs. ?0.9 ± 1.1, P = 0.02) and global efficacy by patient assessment (1.3 ± 1.1 vs. 1.0 ± 1.1, P = 0.047). Intensity of abdominal pain, proportion of patient responders, safety and quality of life scores were similarly affected by OB and placebo. During follow‐up, the therapeutic effect of OB remained greater than placebo in terms of withdrawal rate due to symptom relapse (10% vs. 27%, P = 0.009), global efficacy of treatment and relapse‐free probability (P = 0.038). Conclusions This placebo‐controlled double‐blind study shows that otilonium bromide is safe, well tolerated and superior to placebo in reducing the frequency of abdominal pain, severity of abdominal bloating and protecting from symptom relapse in IBS. These results further confirm that patients with IBS can improve during and following treatment with otilonium bromide.

     

Clinical trial: the efficacy of alverine citrate/simeticone combination on abdominal pain/discomfort in irritable bowel syndrome ‐ a randomized,double‐blind,placebo‐controlled study

Aliment Pharmacol Ther 31 , 615–624

Summary

Background Alverine citrate and simeticone combination has been used for almost 20 years in irritable bowel syndrome (IBS), but supportive scientific evidence of efficacy was limited. Aim To evaluate the efficacy of alverine citrate and simeticone combination in patients with IBS‐related abdominal pain/discomfort. Methods A total of 412 IBS patients meeting ROME III criteria were included in this double‐blind randomized placebo‐controlled study if their abdominal pain/discomfort intensity was at least 60 mm on a 0–100 mm visual analogue scale (VAS) during a 2‐week run‐in treatment‐free period. Patients were randomly assigned through the use of Interactive Voice Response System to receive either alverine citrate 60 mg with simeticone 300 mg three times daily or matching placebo for 4 weeks. Results The full analysis set included 409 patients (71.4% female: mean age: 46.2 ± 13.9 years). At week 4, alverine citrate and simeticone group had lower VAS scores of abdominal pain/discomfort (median: 40 mm vs. 50 mm, P = 0.047) and higher responder rate (46.8% vs. 34.3%, OR = 1.3; P = 0.01) as compared with placebo group. Patient receiving alverine citrate and simeticone reported greater global symptom improvement compared with those receiving placebo (P = 0.0001). Reported adverse events were similar in both groups. Conclusion Alverine citrate/simeticone combination was significantly more effective than placebo in relieving abdominal pain/discomfort in patients with IBS.     

Immune-mediated food reactions in irritable bowel syndrome

Irritable bowel syndrome (IBS) is a chronic functional gastrointestinal disorder characterized by recurrent abdominal pain and an altered defecation pattern. Depending on the criteria used, it affects between 5 and 10% of the general population and has a serious impact on quality of life. Most patients with IBS show an induction or exacerbation of their symptoms, particularly abdominal pain, after eating certain foods. This raises the question of the role played by food in IBS pathophysiology. In this review, we describe the multiple risk factors of IBS, and we give an overview of the role of food as a trigger of IBS, distinguishing between immune and non-immune reactions to food. We finally highlight recent findings identifying an immune-mediated mechanism underlying food-induced abdominal pain in IBS.     

Clinical trial: asimadoline in the treatment of patients with irritable bowel syndrome

Background In models of irritable bowel syndrome (IBS), asimadoline, a kappa‐opioid agonist, improves pain and abnormal bowel function. Aim To evaluate the effects of three doses of asimadoline and placebo in subjects with IBS through a double‐blind, randomized, placebo‐controlled trial. Methods Patients were randomly assigned to receive asimadoline 0.15, 0.5, 1.0 mg or placebo BID for 12 weeks. The primary efficacy measure was number of months of adequate relief of IBS pain or discomfort, with a prospective plan to evaluate adequate relief data by entry baseline pain and subtype. Several other endpoints were also evaluated. Results Five hundred and ninety‐six patients were randomized. In the ITT population, statistically significant improvement on the primary endpoint was not seen. However, in diarrhoea‐predominant IBS patients with at least baseline moderate pain, asimadoline (0.5 mg) produced significant improvement on total number of months with adequate relief of IBS pain or discomfort (46.7% vs. 20.0%), adequate relief of IBS symptoms (46.7% vs. 23.0%), pain scores (week 12: ?1.6 vs. ?0.7), pain free days (42.9% vs. 18.0%), urgency and stool frequency (?2.3 vs. ?0.3). In patients with alternating IBS, significant improvement was seen on adequate relief endpoints. Asimadoline was well tolerated. Conclusion Asimadoline warrants further evaluation as a treatment for IBS.     

Randomised clinical trial: the safety and efficacy of AST-120 in non-constipating irritable bowel syndrome - a double-blind, placebo-controlled study

Aliment Pharmacol Ther 2011; 34: 868–877

Summary

Background There is a need for safe and effective treatment options for irritable bowel syndrome (IBS). AST‐120 (spherical carbon adsorbent) is a non‐absorbed, carbon‐based adsorbent with extensive adsorbing capability for histamine, serotonin and other substances implicated in IBS pathogenesis. Aim To evaluate the efficacy and safety of AST‐120 in non‐constipating forms of IBS. Methods This randomised, double‐blind, placebo‐controlled trial conducted in the US and Belgium enrolled 115 male and female patients fulfilling Rome III criteria for IBS; individuals with predominantly constipation symptoms were excluded. Subjects were randomised to AST‐120 2 g tds or placebo for an 8‐week double‐blind treatment period, followed by a 2‐week single‐blind placebo washout and 8‐week single‐blind active treatment. The primary efficacy endpoint was the proportion of subjects achieving at least a 50% reduction in the number of days with abdominal pain compared with baseline. Results At Week 4, 26.8% of subjects treated with AST‐120 responded on the primary endpoint vs. 10.2% in the placebo arm (P = 0.029); at Week 8 response rates were 32.1 and 25.4% respectively (NS). More AST‐120 treated subjects experienced improvement in bloating and stool consistency. These benefits abated when AST‐120 was replaced by placebo, and resumed once AST‐120 was restarted. The frequency of adverse events with AST‐120 were less than or equal to placebo. Conclusions AST‐120 is safe and well‐tolerated and reduces pain and bloating in non‐constipating IBS, although beneficial effects may be limited in duration. AST‐120 represents a locally acting, non‐absorbed, novel treatment for IBS and warrants further studies.     

Antidepressants in the treatment of irritable bowel syndrome and visceral pain syndromes

Irritable bowel syndrome (IBS) is characterized by abdominal pain associated with disordered defecation, which may include urgency and altered stool frequency. Visceral pain syndromes, including IBS, may be effectively treated by a variety of therapies that modulate the interactions between the central and enteric nervous systems. Clinical observations and preliminary data suggest that antidepressants may be efficacious for the treatment of these syndromes. The tricyclic antidepressants (TCAs) have been utilized most extensively in this area, but there is a need for more rigorous efficacy data. Serotonin, an important neurotransmitter in both the central and enteric nervous systems, modifies both motility and sensation in the gut. Recognition of the importance of serotonin in digestive motility and sensation has sparked interest in the use of agents that modify serotonergic transmission in visceral pain syndromes. Pharmacological therapeutics that modulate the biological amines (serotonin, norepinephrine, dopamine and catecholamines) both peripherally and within the central nervous system may offer more effective therapies for these disorders. The selective serotonin reuptake inhibitors are commonly used in clinical practice, but more rigorous, controlled studies are needed to determine their effects beyond the treatment of psychiatric comorbidity. The newer generation antidepressants may provide additional insight into the pathophysiology of the brain-gut interactions and their relationship to functional bowel disorders, providing new therapeutic interventions.     

Implications of melatonin therapy in irritable bowel syndrome: a systematic review

Irritable bowel syndrome (IBS) is a highly prevalent chronic functional gastrointestinal (GI) disorder associated with abdominal pain and change in bowel habits that its etiology is not known yet. In the recent years, melatonin has been proposed as a possible candidate. In the present work, all clinical or non-clinical data about effects of melatonin in GI tract and IBS obtained from literature without time limit up to August 2010 have been studied and reviewed. Eight clinical trials were reviewed for efficacy and disturbance of melatonin in IBS and other GI disorders. The results showed disturbances in endogenous melatonin concentration in IBS patients and significant benefits of exogenous melatonin in these patients by decreasing abdominal pain and improvement of overall IBS symptom scores. The results of seventeen non-clinical studies showed anxiolytic, anti-inflammatory, anti oxidative and motility regulatory effects of melatonin on GI tract. In conclusion melatonin can be a target of interest in IBS because of its potentials to regulate GI motility.     

Atypical antipsychotics as a possible treatment option for irritable bowel syndrome

Introduction: Irritable bowel syndrome (IBS) is a prevalent functional gastrointestinal disorder (FGID) that is characterised by chronic abdominal pain, discomfort, bloating, and alteration of bowel habits. Although the pathophysiology of IBS is not fully understood, it is believed that psychiatric comorbidities are highly common in such patients. A variety of psychotropic medications are widely used in the treatment of IBS, particularly older antidepressants such as tricyclic antidepressants (TCAs).

Areas covered: With the advent of newer antidepressant classes with better safety and tolerability compared with TCAs, such as serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs), clinicians now have more advanced treatment options for treating IBS. Additionally, some atypical antipsychotics (AAs) have recently received approval for treatment of major depressive disorder (MDD). Some AAs may have potentials based on their pharmacodynamic profile and proven benefit for mood symptoms, pain, anxiety and sleep disturbances. This article describes the potential rationale, clinical data and practical aspects involved in the use of AAs for patients with IBS.

Expert opinion: Atypical antipsychotics (AAs) may have a role in the treatment of irritable bowel syndrome (IBS) based on the currently available findings, although there is no clear evidence, and a number of clinical issues to be addressed in the use of AAs for the treatment of IBS.     

消化门诊肠易激综合征患者肠外症状分析

目的了解肠易激综合征(IBS)患者临床症状表现,尤其是肠外症状,提高IBS诊断率。方法对2010年12月至2011年7月郑州大学第一附属医院消化内科门诊就诊并按照罗马Ⅲ标准诊断为IBS的患者进行问卷调查。共调查866例,收回问卷847份作为统计病例。结果 IBS是一种复杂的身心疾病,除表现在胃肠功能紊乱,腹痛、腹部不适,排便性状、频率改变外,还表现有咽部不适及异物感,口干、口苦、口臭、无味觉,功能性消化不良,无饥饿感,腰背及肌肉酸、痛、纤维肌痛综合征等全身不明原因的疼痛,手心、脚心灼热等功能性低热,肢体凉、畏寒,失眠、头痛,心烦,慢性疲劳综合征,体重减轻,尿道不适,性交困难等肠外表现等。结论 IBS患者多反复就诊于综合医院的各个科室,部分临床医生对IBS复杂的临床症状尤其是肠道外症状认识少,鉴别困难,使IBS诊断率低,治疗效果差。     

Clinical trial: a randomized trial comparing fluoroscopy guided percutaneous technique vs. endoscopic ultrasound guided technique of coeliac plexus block for treatment of pain in chronic pancreatitis

Background Coeliac plexus block (CPB) is a management option for pain control in chronic pancreatitis. CPB is conventionally performed by percutaneous technique with fluoroscopic guidance (PCFG). Endoscopic ultrasound (EUS) is increasingly used for CPB as it offers a better visualization of the plexus. There are limited data comparing the two modalities. Aim To compare the pain relief in chronic pancreatitis among patients undergoing CPB either by PCFG technique or by EUS guided technique. Methods Chronic pancreatitis patients with abdominal pain requiring daily analgesics for more than 4 weeks were included. Fifty six consecutive patients (41 males, 15 females) participated in the study. EUSG‐CPB was performed in 27 and PCFG‐CPB in 29 patients. In both the groups, 10 mL of Bupivacaine (0.25%) and 3 mL of Triamcinolone (40 mg) were given on both sides of the coeliac artery through separate punctures. Results Pre and post procedure pain scores were obtained using a 0‐10 visual analogue scale. Improvement in pain scores was seen in 70% of subjects undergoing EUS‐CPB and 30% in Percutaneous‐ block group (P = 0.044). Conclusions EUS‐guided coeliac block appears to be better than PCFG‐CPB for controlling abdominal pain in patients with chronic pancreatitis.